6-11 Bicyclic erythromycin derivatives

ABSTRACT

The present invention discloses compounds of formulaes I, II, III, or IV, or a racemate, enantiomer, regioisomer, salt, ester or prodrug thereof: 
                         
which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/534,885, filed on Jan. 7, 2004. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity and useful in the treatment and prevention ofbacterial infections. More particularly, the invention relates to 6-11bicyclic macrolide, ketolide, and anhydrolide derivatives, compositionscontaining such compounds and methods for using the same, as well asprocesses for making such compounds.

BACKGROUND OF THE INVENTION

Macrolide antibiotics play a therapeutically important role,particularly with the emergence of new pathogens. Structural differencesare related to the size of the lactone ring and to the number and nature(neutral or basic) of the sugars. Macrolides are classified according tothe size of the lactone ring (12, 14, 15 or 16 atoms). The macrolideantibiotic family (14-, 15- and 16-membered ring derivatives) shows awide range of characteristics (antibacterial spectrum, side-effects andbioavailability). Among the commonly used macrolides are erythromycin,clarithromycin, and azithromycin. Macrolides possessing a 3-oxo moietyin place of the 3-cladinose sugar are known as ketolides and have shownenhanced activity towards gram-negative bacteria and macrolide resistantgram-positive bacteria. Macrolides possessing a degree of unsaturationbetween carbons 2 and 3 or between carbons 3 and 4 of the erythromycinmacrocycle are known as anhydrolides. The search for macrolide compoundswhich are active against MLS_(B)-resistant strains(MLS_(B)=Macrolides-Lincosamides-type B Streptogramines) has become amajor goal, together with retaining the overall profile of themacrolides in terms of stability, tolerance and pharmacokinetics.

International Application WO 97/42205 of Elliott et al, published Nov.13, 1997, discloses 3-descladinose-2,3-anhydroerythromycin derivativeshaving a cyclic carbamate and cyclic carbazate basic nuclear structure.Further details were also disclosed in J. Med Chem., 41, pp1651-1659(1998) and J. Med Chem., 41, pp 1660-1670 (1998) by Elliott etal, and by Griesgraber et al, respectively.

U.S. Pat. No. 5,444,051 discloses certain6-O-substituted-3-oxoerythromycin A derivatives. PCT application WO97/10251, published Mar. 20, 1997, discloses intermediates useful forpreparation of 6-O-methyl 3-descladinose erythromycin derivatives. U.S.Pat. No. 5,631,355 discloses certain tricyclic 6-O-methyl 3-oxoerythromycin derivatives. U.S. Pat. No. 5,527,780 discloses certainbicyclic 6-O-methyl-3-oxo erythromycin A derivatives (Agouridas,ROUSSEL) corresponding to EP application 596802, published May 11, 1994.U.S. Pat. Nos. 5,866,549 and 6,075,011, and PCT application WO 00/78773,published Dec. 28, 2000, disclose certain 6-O-substituted erythromycinderivatives. U.S. Pat. No. 6,124,269 and PCT application WO 00/62783,published Oct. 26, 2000, disclose certain 2-halo-6-O-substitutedketolide derivatives. U.S. Pat. No. 6,046,171 and PCT application WO99/21864, published May 6, 1999, disclose certain 6,11-bridgederythromycin derivatives.

PCT Application WO 03/095466 A1, published Nov. 20, 2003 and PCTApplication WO 03/097659 A1, published Nov. 27, 2003 disclose a seriesof bicyclic erythromycin derivatives.

SUMMARY OF THE INVENTION

The present invention provides a novel class of C6-C11 bridgederythromycin derivatives which possess antibacterial activity.

In one aspect of the present invention there are provided novel bridgederythromycin compounds represented by the formulae as illustrated below:

or their racemates, enantiomers, regioisomers, salts, esters or prodrugsthereof, wherein

A and B are independently selected from the group consisting of:hydrogen, deuterium, halogen, R₁, OR₁, S(O)_(n)R₁, —NR₁C(O)R₁,—NR₁C(O)NR₃R₄, —NHS(O)_(n)R₁, —CONR₃R₄, and NR₃R₄;

R₁ and R₂ are independently selected from the group consisting of:hydrogen, acyl, silane, a substituted or unsubstituted, saturated orunsaturated aliphatic group, a substituted or unsubstituted, saturatedor unsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, or asubstituted or unsubstituted heterocyclic group;

Each of R₃ and R₄ is independently selected from the group consistingof: hydrogen, acyl, a substituted or unsubstituted, saturated orunsaturated aliphatic group, a substituted or unsubstituted, saturatedor unsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, asubstituted, or unsubstituted heterocyclic group; or can be takentogether with the nitrogen atom to which they are attached to form asubstituted or unsubstituted heterocyclic or heteroaromatic ring;

Each of R₂₀ and R₂₁ is independently selected from the group consistingof: hydrogen, acyl, a substituted or unsubstituted, saturated orunsaturated aliphatic group, a substituted or unsubstituted, saturatedor unsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, asubstituted, or unsubstituted heterocyclic group, provided that R₂₀ andR₂₁ cannot be methyl and hydrogen, methyl and methyl, or methyl andhalogen;

or R₂₀ and R₂₁ taken together with the carbon atom to which they areattached form a substituted or unsubstituted alicylic or substituted orunsubstituted heterocyclic ring;

or A and B, taken together with the carbon atom to which they areattached, form a substituted or unsubstituted alicyclic, aromatic,heterocyclic or heteroaromatic ring;

or A and B, taken together with the carbon atom to which they areattached, are selected from the group consisting of: CO, C═CHR₁, C═NR₁,C═NOR₁, C═NO(CH₂)_(m)R₁, C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂,C═NNHS(O)_(n)R₁, or C═N—N═CHR₁;

M is selected from the group consisting of: hydrogen, R₁, C(O)R₁,S(O)_(n)R₁, or C(O)NR₃R₄; provided that M is not hydrogen for compoundsof formula I;

L is selected from the group consisting of: hydrogen, a substituted orunsubstituted, saturated or unsaturated aliphatic group, a substitutedor unsubstituted, saturated or unsaturated alicyclic group, asubstituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, or a substituted or unsubstitutedheterocyclic group;

X and Y are independently selected from the group consisting of:hydrogen, deuterium, halogen, R₁, OR₁, S(O)_(n)R₁, —NR₁C(O)R₁,—NR₁C(O)NR₃R₄, —NR₁S(O)_(n)R₁, —C(O)NR₃R₄, and —NR₃R₄;

or X and Y, taken together with the carbon atom to which they areattached, are selected from the group consisting of: CO, C═CHR₁, C═NR₁,C═NC(O)R₁, C═NOR₁, C═NO(CH₂)_(m)R₁, C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂,C═NNHS(O)_(n)R₁, C═N—N═CHR₁, C═N—NO₂, or C═N—ONO;

-   -   one of U or V is hydrogen and the other is independently        selected from the group consisting of: R₁, OR₁, OC(O)R₁,        OC(O)NR₃R₄, S(O)_(n)R₁, or

or U and V, taken together with the carbon atom to which they areattached, are C═O;

one of J or G is hydrogen and the other is selected from: R₁, OR₁, orNR₃R₄;

or, J and G, taken together with the carbon atom to which they areattached, are selected from: C═O, C═NR₁, C═NOR₁, C═NO(CH₂)_(m)R₁,C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, or C═N—N═CHR₁;

-   -   W is NR₃R₄;    -   Z is hydrogen, alkyl or halogen;    -   R_(p) is hydrogen, hydroxy protecting group or hydroxy prodrug        group;    -   m is an integer; and    -   n is 0, 1, or 2.

In another embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of any compound of the present invention in combination with apharmaceutically acceptable carrier or excipient. In yet anotherembodiment of the invention are methods of treating antibacterialinfections in a subject with said pharmaceutical compositions. Suitablecarriers and methods of formulation are also disclosed.

In a further aspect of the present invention there are providedprocesses for the preparation of any 6,11 bridged erythromycinderivative of formulas I, II, III, or IV via any synthetic routedelineated herein.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the present invention is a compound of formula Ias defined herein, or a racemate, enantiomer, regioisomer,pharmaceutically acceptable salt, ester, or prodrug thereof.

A second embodiment of the present invention is a compound of formula IIas defined herein, or a racemate, enantiomer, regioisomer,pharmaceutically acceptable salt, ester, or prodrug thereof.

A third embodiment of the present invention is a compound of formula IIIas defined herein, or a racemate, enantiomer, regioisomer,pharmaceutically acceptable salt, ester, or prodrug thereof.

A fourth embodiment of the present invention is a compound of formula IVas defined herein, or a racemate, enantiomer, regioisomer,pharmaceutically acceptable salt, ester, or prodrug thereof.

Representative subgenera of the present invention are:

-   A compound according to formula I, wherein M is not hydrogen;-   A compound according to formula I, II, III, or IV wherein A and B    taken together with the carbon atom to which they are attached are    C═N—O—CH₂—R₁, where R₁ is:

1. a substituted pyridyl;

2. a pyridyl substituted with pyrazole;

3. C≡C-(pyridyl) or C≡C-(substituted pyridyl);

4. C≡C-(2-amino-6-pyridyl);

5. a pyridyl substituted with a substituted pyridyl;

6. a substituted thiophenyl; or

7. a thiophenyl substituted with a substituted pyridyl;

-   A compound according to formula I, II, III, or IV, wherein A and B    taken together with the carbon atom to which they are attached are    C═CH—R₁;-   A compound according to formula I, II, III, or IV, wherein A and B    taken together with the carbon atom to which they are attached are    C═CH—R₁ and X and Y taken together with the carbon atom to which    they are attached are C═N-Q, where Q is R₁, C(O)R₁, OR₁,    O(CH₂)_(m)R₁, NHR₁, NHCOR₁, NHCONR₁R₂, NHS(O)_(n)R₁, N═CHR₁, NO₂, or    ONO;-   A compound according to formula I, II, III, or IV wherein A and B    taken together with the carbon atom to which they are attached are    C═CH—R₁ and X and Y taken together with the carbon atom to which    they are attached are C═N—Ac;-   A compound according to formula I, II, III, or IV wherein X and Y    taken together with the carbon atom to which they are attached are    C═N—R₁;-   A compound according to formula I, II, III, or IV wherein X and Y    taken together with the carbon atom to which they are attached are    C═N—Ac;-   A compound according to formula I, II, III, or IV wherein A and B    taken together with the carbon to which they are attached are C═O    and X and Y taken together with the carbon atom to which they are    attached are C═N—R₁;-   A compound according to formula I, II, III, or IV wherein A and B    taken together with the carbon to which they are attached are C═O, X    and Y taken together with the carbon atom to which they are attached    are C═N—R₁, and W is N(CH₃)₂;-   A compound according to formula I, II, III, or IV wherein A and B    taken together with the carbon to which they are attached are C═O, X    and Y taken together with the carbon atom to which they are attached    are C═N—Ac, and W is N(CH₃)₂; or-   A compound according to formula I, II, III, or IV wherein A and B    taken together with the carbon atom to which they are attached are    C═N—O—R₁, X and Y taken together with the carbon atom to which they    are attached are C═N—R₁, L is ethyl, and W is N(CH₃)₂.

A Compound of Formula A:

-   -   wherein M, U, V, W, X, Y, Z, R₁ and R_(p) are as previously        defined.

Representative compounds according to the invention are those selectedfrom the group consisting of:

-   -   (1) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —C(O)NH₂, X and Y        taken together with the carbon atom to which they are attached        are C═N—Ac, U and V taken together with the carbon atom to which        they are attached are C═O, Z is hydrogen, L is ethyl, W is        N(CH₃)₂, and R_(p) is Ac;    -   (2) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are C═CH₂, M is        —C(O)NHCH₂CH═CH₂, X and Y taken together with the carbon atom to        which they are attached are C═N—Ac, U and V taken together with        the carbon atom to which they are attached are C═O, Z is        hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen;    -   (3) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and        Y taken together with the carbon atom to which they are attached        are C═N—Ac, U is hydrogen, V is OH, Z is hydrogen, L is ethyl, W        is N(CH₃)₂, and R_(p) is Ac;    -   (4) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and        Y taken together with the carbon atom to which they are attached        are C═N—Ac, U is hydrogen, V is OH, Z is hydrogen, L is ethyl, W        is N(CH₃)₂, and R_(p) is Ac;    -   (5) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and        Y taken together with the carbon atom to which they are attached        are C═N—Ac, U and V taken together with the carbon atom to which        they are attached are C═O, Z is hydrogen, L is ethyl, W is        N(CH₃)₂, and R_(p) is Ac;    -   (6) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and        Y taken together with the carbon atom to which they are attached        are C═N—Ac, U and V taken together with the carbon atom to which        they are attached are C═O, Z is hydrogen, L is ethyl, W is        N(CH₃)₂, and R_(p) is hydrogen;    -   (7) compounds of formulaes III and IV, wherein A and B taken        together with the carbon atom to which they are attached are        C═CH₂, M is hydrogen, X and Y taken together with the carbon        atom to which they are attached are C═N—Ac, L is ethyl, W is        N(CH₃)₂, and R_(p) is hydrogen;    -   (8) compounds of formulaes III and IV, wherein A and B taken        together with the carbon atom to which they are attached are        C═CH—CH═CH-phenyl, M is hydrogen, X and Y taken together with        the carbon atom to which they are attached are C═N—Ac, L is        ethyl, W is N(CH₃)₂, and R_(p) is Ac;    -   (9) compounds of formula III and IV, wherein A and B taken        together with the carbon atom to which they are attached are        C═CH—CH═CH-phenyl, M is hydrogen, X and Y taken together with        the carbon atom to which they are attached are C═N—Ac, W is        N(CH₃)₂, and R_(p) is hydrogen;    -   (10) compounds of formula III, wherein A is OH, B is CH₂OH, M is        hydrogen, X and Y taken together with the carbon atom to which        they are attached are C═N—Ac, L is ethyl, W is N(CH₃)₂ and        R_(p)═Ac;    -   (11) compounds of formula III, wherein A is OH, B is CH₂OH, M is        hydrogen, X and Y taken together with the carbon atom to which        they are attached are C═N—Ac, L is ethyl, W is N(CH₃)₂ and M and        R_(p) are hydrogen;    -   (12) compounds of formula II, wherein A, V, and R₂₁ are OH, B is        CH₂OH, M and U are hydrogen, X and Y taken together with the        carbon atom to which they are attached are C═N—Ac, L is ethyl, W        is N(CH₃)₂, R₂₀ is methyl, and R_(p)═Ac;    -   (13) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are C═CH₂, M is        —C(O)N(CH₂CH═CH₂)(CONHCH₂CH═CH₂), X and Y taken together with        the carbon atom to which they are attached are C═N—Ac, U and V        taken together with the carbon atom to which they are attached        are C═O, Z is F, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac;    -   (14) compound of formula I, wherein A and B taken together with        the carbon atom to which they are attached are C═CH₂, M is        —C(O)N(CH₂CH═CH₂)(CONHCH₂CH═CH₂), X and Y taken together with        the carbon atom to which they are attached are C═O, U and V        taken together with the carbon atom to which they are attached        are C═O, Z is F, L is ethyl, W is N(CH₃)₂, and R_(p) is        hydrogen;    -   (15) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are C═CH₂, X and Y        taken together with the carbon atom to which they are attached        are C═NAc, U and V taken together with the carbon atom to which        they are attached are C═O, M=R₂₀═H, R₂₁═CH₂OH, L is ethyl, W is        N(CH₃)₂, and R_(p)═Ac;    -   (16) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are C═CH₂, X and Y        taken together with the carbon atom to which they are attached        are C═NAc, U and V taken together with the carbon atom to which        they are attached are C═O, M=R₂₀═H, R₂₁═CH₂OCH₃, L is ethyl, W        is N(CH₃)₂, and R_(p) is hydrogen;    -   (17) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are C═CH₂, X and Y        taken together with the carbon atom to which they are attached        are C═NAc, U and V taken together with the carbon atom to which        they are attached are C═O, M=R₂₀═H,        R₂₁═CH₂—NH—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], L is ethyl, W        is N(CH₃)₂, and R_(p) is hydrogen;    -   (18) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are C═CH₂, X and Y        taken together with the carbon atom to which they are attached        are C═NAc, U and V taken together with the carbon atom to which        they are attached are C═O, M=R₂₀═R₂₁═H, L is ethyl, W is        N(CH₃)₂, and R_(p) is hydrogen;    -   (19) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together        with the carbon atom to which they are attached are C═NAc, U and        V taken together with the carbon atom to which they are attached        are C═O, M=R₂₀═H, R₂₁═CH₂OH, L is ethyl, W is N(CH₃)₂, and        R_(p)═Ac;    -   (20) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together        with the carbon atom to which they are attached are C═NAc, U and        V taken together with the carbon atom to which they are attached        are C═O, M=R₂₀═R₂₁═H, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac;    -   (21) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together        with the carbon atom to which they are attached are C═NAc, U and        V taken together with the carbon atom to which they are attached        are C═O, M=R₂₀═R₂₁═R_(p)═H, L is ethyl, and W is N(CH₃)₂;    -   (22) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together        with the carbon atom to which they are attached are C═NAc, U and        V taken together with the carbon atom to which they are attached        are C═O, M=R₂₀═H, R₂₁═CH₂CH═CH₂, L is ethyl, W is N(CH₃)₂, and        R_(p)═Ac;    -   (23) compound of formula II, wherein A and B taken together with        the carbon atom to which they are attached are        C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together        with the carbon atom to which they are attached are C═NAc, U and        V taken together with the carbon atom to which they are attached        are C═O, M=R₂₀═H, R₂₁═CH₂CH═CH₂, L is ethyl, W is N(CH₃)₂, and        R_(p) is hydrogen;

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound delineated herein, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising a combination of two or more compounds delineatedherein, or a pharmaceutically acceptable salt, ester, or prodrugthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound delineated herein incombination with one or more antibiotics known in the art (such aspenicillin, amoxicillin, azithromycin, erythromycin, ciproflaxin,telithromycin, cethromycin, and the like) or a pharmaceuticallyacceptable salt, ester, or prodrug thereof, with a pharmaceuticallyacceptable carrier or excipient.

Yet an additional aspect of the present invention relates to a method oftreating a subject (e.g., mammal, human, horse, dog, cat, fish) havingbacterial infection or disease or disease symptom related to having abacterial infection (including diseases delineated herein). The methodincludes administering to the subject (including a subject identified asin need of such treatment) an effective amount of a compound describedherein, or a composition described herein to produce such effect.Identifying a subject in need of such treatment can be in the judgmentof a subject or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

Also within the scope of this invention is a packaged product. Thepackaged product includes a container, one of the aforementionedcompounds in the container, and a legend (e.g., a label or an insert)associated with the container and indicating administration of thecompound for treating a disorder associated with bacterial infection,including the diseases delineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” is non-aromatic moiety that may contain anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic and preferably contains betweenabout 1 and about 24 carbon atoms, more typically between about 1 andabout 12 carbon atoms. In addition to aliphatic hydrocarbon groups,aliphatic groups include, for example, polyalkoxyalkyls, such aspolyalkylene glycols, polyamines, and polyimines, for example. Suchaliphatic groups may be further substituted.

The terms “C₁-C₃ alkyl,” “C₁-C₆ alkyl,” or “C₁-C₁₂ alkyl,” as usedherein, refer to saturated, straight- or branched-chain hydrocarbonradicals containing between one and three, one and twelve, or one andsix carbon atoms, respectively. Examples of C₁-C₃ alkyl radicals includemethyl, ethyl, propyl and isopropyl radicals; examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl, propyl,butyl, pentyl, and hexyl radicals; and examples of C₁-C₁₂ alkyl radicalsinclude, but are not limited to, ethyl, propyl, propyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl radicals and the like.

The term “substituted alkyl,” as used herein, refers to an alkyl, suchas a C₁-C₁₂ alkyl or C₁-C₆ alkyl group, substituted by one, two, threeor more aliphatic substituents.

Suitable aliphatic or aromatic substituents include, but are not limitedto, —F, —Cl, —Br, —I, —OH, protected hydroxy, aliphatic ethers, aromaticethers, oxo, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen (such as perhaloalkyls), C₂-C₁₂-alkenyl optionally substitutedwith halogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH —C₁-C₁₂-alkyl, —NH —C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkynyl, —NH —C₃-C₁₂-cycloalkyl, —NH -aryl, —NH -heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —CO₂—C₁-C₁₂-alkyl,—CO₂—C₂-C₁₂-alkenyl, —CO₂—C₂-C₁₂-alkynyl, —CO₂—C₃-C₁₂-cycloalkyl,—CO₂-aryl, —CO₂-heteroaryl, —CO₂-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH— aryl, —OCONH— heteroaryl, —OCONH—heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₂-C₁₂-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂— aryl, —NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH— aryl, —SO₂NH— heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkylsand the like can be further substituted.

The terms “C₂-C₁₂ alkenyl” or “C₂-C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, alkadienes and the like.

The term “substituted alkenyl,” as used herein, refers to a “C₂-C₁₂alkenyl” or “C₂-C₆ alkenyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The terms “C₂-C₁₂ alkynyl” or “C₂-C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of a single hydrogen atom. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to a “C₂-C₁₂alkynyl” or “C₂-C₆ alkynyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The terms “aryl” or “aromatic,” as used herein, refer to a mono- orbicyclic carbocyclic ring system having one or two aromatic ringsincluding, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, idenyl and the like.

The terms “substituted aryl” or “substituted aromatic,” as used herein,refer to an aryl group, as previously defined, substituted by one, two,three or more aromatic substituents.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkyl residue.Examples include, but are not limited to, benzyl, phenethyl and thelike.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by one, two, three or morearomatic substituents.

The terms “heteroaryl” or “heteroaromatic,” as used herein, refers to amono-, bi-, or tri-cyclic aromatic radical or ring having from five toten ring atoms of which at least one ring atom is selected from S, O andN; zero, one, two, three or more ring atoms are additional heteroatomsindependently selected from S, O and N; and the remaining ring atoms arecarbon, wherein any N or S contained within the ring may be optionallyoxidized. Heteroaryl includes, but is not limited to, pyridinyl,pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl,tetrazolyl and the like. The heteroaromatic ring may be bonded to thechemical structure through a carbon or hetero atom.

The terms “substituted heteroaryl” or “substituted heteroaromatic,” asused herein, refer to a heteroaryl group as previously defined,substituted by one, two, three or four aromatic substituents.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl,and bicyclo [2.2.2] octyl.

The term “substituted alicyclic” group as previously defined,substituted by one, two, three or more aliphatic substituents.

The terms “heterocyclic” as used herein, refers to a non-aromatic 5-, 6-or 7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, (iv) any ofthe above rings may be fused to a benzene ring, and (v) the remainingring atoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, tetrahydrofuryl, and the like.

The term “substituted heterocyclic,” as used herein, refers to aheterocyclic group, as previously defined, substituted by one, two,three or more aliphatic substituents.

The term “heteroarylalkyl,” as used herein, refers to a heteroaryl groupattached to the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkylresidue. Examples include, but are not limited to, pyridinylmethyl,pyrimidinylethyl and the like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement of one, two, or three or more aromatic substituents.

The term “C₁-C₃-alkylamino,” as used herein, refers to one or twoC₁-C₃-alkyl groups, as previously defined, attached to the parentmolecular moiety through a nitrogen atom. Examples of C₁-C₃-alkylaminoinclude, but are not limited to, methylamino, dimethylamino, ethylamino,diethylamino, and propylamino.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl) (C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e., an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl) (C₁-C₁₂ alkyl), —C(O)NH₂,—NHC(O)(C₁-C₁₂ alkyl), —N(C₁-C₁₂ alkyl)C(O)(C₁-C₁₂ alkyl) and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent” or “protic solvent,” as usedherein, refers to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, water and the like. Such solvents are well known to thoseskilled in the art, and it will be obvious to those skilled in the artthat individual solvents or mixtures thereof may be preferred forspecific compounds and reaction conditions, depending upon such factorsas the solubility of reagents, reactivity of reagents and preferredtemperature ranges, for example. Further discussions of protogenicsolvents may be found in organic chemistry textbooks or in specializedmonographs, for example: Organic Solvents Physical Properties andMethods of Purification, 4th ed., edited by John A. Riddick et al., Vol.II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid or inorganic acid. Examples of pharmaceuticallyacceptable nontoxic acid addition salts include, but are not limited to,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid lactobionic acid or malonic acid or byusing other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infections”; includes, but is not limited to,bacterial infections and protozoa infections that occur in mammals, fishand birds as well as disorders related to bacterial infections andprotozoa infections that may be treated or prevented by administeringantibiotics such as the compounds of the present invention. Suchbacterial infections and protozoa infections and disorders related tosuch infections include, but are not limited to, the following:pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, cysticfibrosis (CF) and mastoiditis related to infection by Streptococcuspneumoniae, Haemophilus influenzae, Moraxella catarrhalis,Staphylococcus aureus, Peptostreptococcus spp. or Pseudomonas spp.;pharynigitis, rheumatic fever, and glomerulonephritis related toinfection by Streptococcus pyogenes, Groups C and G streptococci,Clostridium diptheriae, or Actinobacillus haemolyticum; respiratorytract infections related to infection by Mycoplasma pneumoniae,Legionella pneumophila, Streptococcus pneumoniae, Haemophilusinfluenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissueinfections, abscesses and osteomyelitis, and puerperal fever related toinfection by Staphylococcus aureus, coagulase-positive staphylococci(i.e., S. epidermidis, S. hemolyticus, etc.), S. pyogenes, S.agalactiae, Streptococcal groups C-F (minute-colony streptococci),viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus (food poisoning and Toxic shocksyndrome), or Groups A, S. and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; tuberculosisdisease related to infection by Mycobacterium tuberculosis;gastroenteritis related to infection by Campylobacter jejuni; intestinalprotozoa related to infection by Cryptosporidium spp. odontogenicinfection related to infection by viridans streptococci; persistentcough related to infection by Bordetella pertussis; gas gangrene relatedto infection by Clostridium perfringens or Bacteroides spp.; Skininfection by S. aureus, Propionibacterium acne; atherosclerosis relatedto infection by Helicobacter pylori or Chlamydia pneumoniae; or thelike.

Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include, butare not limited to, the following: bovine respiratory disease related toinfection by P. haemolytica., P. multocida, Mycoplasma bovis, orBordetella spp.; cow enteric disease related to infection by E. coli orprotozoa (i.e., coccidia, cryptosporidia, etc.), dairy cow mastitisrelated to infection by S. aureus, S. uberis, S. agalactiae, S.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuropneumoniae.,P. multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa (i.e.neosporium); urinary tract infection in dogs and cats related toinfection by E. coli; skin and soft tissue infections in dogs and catsrelated to infection by S. epidermidis, S. intermedius, coagulase neg.Staphylococcus or P. multocida; and dental or mouth infections in dogsand oats related to infection by Alcaligenes spp., Bacteroides spp.,Clostridium spp., Enterobacter spp., Eubacterium spp.,Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., and Trichomonas spp. or Prevotella spp. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford at al., “TheSanford Guide To Antimicrobial Therapy,” 26th Edition, (AntimicrobialTherapy, Inc., 1996).

Antibacterial Activity

Susceptibility tests can be used to quantitatively measure the in vitroactivity of an antimicrobial agent against a given bacterial isolate.Compounds are tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) isdetermined in 96 well microtiter plates utilizing the appropriateMueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.Antimicrobial agents are serially diluted (2-fold) in DMSO to produce aconcentration range from about 64 μg/ml to about 0.03 μg/ml. The dilutedcompounds (2 μl/well) are then transferred into sterile, uninoculatedCAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculumfor each bacterial strain is standardized to 5×10⁵ CFU/mL by opticalcomparison to a 0.5 McFarland turbidity standard. The plates areinoculated with 10 μl/well of adjusted bacterial inoculum. The 96 wellplates are covered and incubated at 35+/−2° C. for 24 hours in ambientair environment. Following incubation, plate wells are visually examinedby Optical Density measurement for the presence of growth (turbidity).The lowest concentration of an antimicrobial agent at which no visiblegrowth occurs is defined as the MIC. The compounds of the inventiongenerally demonstrated an MIC in the range from about 64 μg/ml to about0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A4 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

The invention further provides compositions and methods of treatingpatients suffering from an inflammatory condition comprisingadministering to a patient in need thereof, a therapeutically effectiveamount of at least one compound of the invention. Specific examples ofinflammatory conditions treatable according to the invention include,but are not limited to, scleritis; epi-scleritis; allergicconjunctivitis; pulmonary inflammatory diseases, particularly CF,asthma, chronic obstructive pulmonary disease (COPD), allergicbronchopulmonary aspergillosis (ABPA), and sarcoidosis;procto-sigmoiditis; allergic rhinitis; arthritis; tendonitis; apthousstomatitis; and inflammatory bowel disease.

The invention further provides compositions and methods for i)prophylactic treatment of those patients susceptible to the symptoms CFincluding pulmonary infection and inflammation associated with CF, ii)treatment at the initial onset of symptoms of pulmonary infection andinflammation associated with CF, and iii) treatment of ongoing orrelapsing symptoms of infection and inflammation associated with CF. Inaccordance with the invention a compound of the invention, isadministered to a patient in need of treatment for CF, in amountsufficient to prevent, diminish or eradicate symptoms of CF includingchronic pulmonary inflammation and infection.

Pharmaceutical Compositions.

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43,650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

According to the methods of treatment of the present invention,bacterial infections, cystic fibrosis and inflammatory conditions aretreated or prevented in a patient such as a human or another animal byadministering to the patient a therapeutically effective amount of acompound of the invention, in such amounts and for such time as isnecessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically exipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The pharmaceutical compositions of this invention can be administeredorally to fish by blending said pharmaceutical compositions into fishfeed or said pharmaceutical compositions may be dissolved in water inwhich infected fish are placed, a method commonly referred to as amedicated bath. The dosage for the treatment of fish differs dependingupon the purpose of administration (prevention or cure of disease) andtype of administration, size and extent of infection of the fish to betreated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kgof body weight of fish may be administered per day, either at one timeor divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

-   -   Ac for acetyl;    -   AIBN for azobisisobutyronitrile;    -   Bu₃SnH for tributyltin hydride;    -   CDI for carbonyldiimidazole;    -   dba for dibenzylidene acetone;    -   dppb for diphenylphosphino butane;    -   DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;    -   DEAD for diethylazodicarboxylate;    -   DMAP for dimethylaminopyridine;    -   DMF for dimethyl formamide;    -   DPPA for diphenylphosphoryl azide;    -   EtOAc for ethyl acetate;    -   MeOH for methanol;    -   Ms for mesylate or O—SO₂—CF₃;    -   NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;    -   NMMO for N-methylmorpholine N-oxide;    -   TEA for triethylamine;    -   THF for tetrahydrofuran;    -   TPP or PPh₃ for triphenylphosphine;    -   MOM for methoxymethyl;    -   Boc for t-butoxycarbonyl;    -   Bz for benzoyl;    -   Bn for benzyl;    -   Ph for phenyl;    -   POPd for dihydrogen        dichlorobis(di-tert-butylphosphinito-κP)palladate(II);    -   TBS for tert-butyl dimethylsilyl; or    -   TMS for trimethylsilyl.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemesillustrating the methods by which the compounds of the invention may beprepared.

A preferred intermediate for the preparation of the compounds of thepresent invention are compounds of formula (1-1):

Compounds of formula (1-1), as well as methods of preparing suchcompounds, are described in U.S. application Ser. Nos. 10/429,485 and10/436,602.

Scheme 1 illustrates a process of preparing compounds of the presentinvention, comprising the step of treating a compound of formula (1-1)with a tert-butyl allyl carbonate (1-2) in the presence of a palladiumcatalyst [Pd(0) or Pd(II)] and an additive, in aprotic solvents fromabout room temperature to about 100° C. to provide a compound of formula(1-4) (see (a) Trost, B. M. Angew. Chem. Int. Ed. Eng. 1989, 28, 11179;(b) Heck, Palladium Reagents in Organic Synthesis, Academic Press: NewYork, 1985, Chapter 1; (c) Tsuji, Tetrahedron Lett. 1992, 33, 2987).Compound (1-4) may further be derivatized through treatment with an arylhalide or aryl triflate in the presence of a palladium catalyst [Pd(0)or Pd(II)] with a phosphorus ligand and a base such as TEA or K₂CO₃ toprovide compound (1-3) (see (a) Heck, Palladium Reagents in OrganicSynthesis, Academic Press: New York, 1985, Chapter 1; (b) Sonogashira,Comprehensive Organic Synthesis, Volume 3, Chapters 2, 4; (c)Sonogashira, Synthesis 1977, 777).

Alternatively, compound (1-3) can be obtained by treating compound (1-1)with substituted tert-butyl allyl carbonate of formula (1-2), wherein R₁is as previously defined, in the presence of a palladium catalyst and aphosphine additive. Compounds of formulas (1-3) or (1-4) may optionallybe hydrogenated with Palladium on carbon, Palladium black, Platinumoxide or the like under 1-4 atm pressure of hydrogen in a solvent suchas methanol, ethanol, ethyl acetate at a temperature from about 0° C. toabout 50° C. for less than 36 hours to provide the correspondingsaturated compounds.

Scheme 2 illustrates cross metathesis reaction of a compound of formula(1-4) with alkenyl derivatives of formula CH₂═CH—(CH₂)_(n)—R, usingruthenium catalysts in an aprotic solvent such as methylene chloride,THF, chloroform, DMF, or acetonitrile, at from 0° C. to 80° C. for lessthan 48 hours to produce compound (2-1) (see (a) J. Org. Chem. 2000, 65,2204-2207; (b) Reviews: Synlett. 1999, 2, 267; (c) Reviews: Ivin, K. J.;Mol, J. C. Olefin Metathesis and Metathesis Polymerization, 2^(nd) ed.;Academic Press: New York, 1997; (d) J. Org. Chem. 1999, 64, 4798-4816;(e) Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056; (f) Tetrahedron1998, 54, 4413-4450). Compound (2-1) may optionally be hydrogenated asdescribed in Scheme 1.

As illustrated in Scheme 3, Step A allyl compounds of formula (1-4) canbe oxidatively cleaved to form an aldehyde compound of formula (3-1).Oxidative cleavage may be performed by, for example, ozonolysis or bytreatment with an oxidant followed by cleaving reagent. Ozonolysis maybe achieved by treating the alkene of a compound of formula (1-4) withozone followed by decomposition of the ozonide with the appropriatereducing agent. Suitable reducing agents for this process include, butare not limited to, dimethyl sulfide, zinc, trivalent phosphorouscompounds, sodium sulfite, and the like. The reaction is typicallycarried out in an inert solvent such as, but not limited to, methanol,ethanol, ethyl acetate, glacial acetic acid, chloroform, methylenechloride or hexanes or mixtures thereof, preferably methanol, preferablyat −78° to −20° C. Preferred reducing agents include, but are notlimited to, triphenylphosphine, trimethyl phosphite, thiourea, anddimethyl sulfide, preferably triphenylphosphine. A more thoroughdiscussion of ozonolysis and the conditions there for can be found in J.March “Advanced Organic Chemistry” 4^(th) ed., Wiley & Son, Inc, 1992.

An alternative method for the preparation of a compound of formula (3-1)involves dihydroxylation of a compound of formula (1-4) by an oxidantfollowed by treatment with a cleaving reagent. The glycol is firstprepared by reacting alkene with an oxidant. Suitable oxidants for thepresent process include, but are not limited to, permanganate ion andosmium tetroxide. The process may utilize stochiometric amounts ofosmium tetroxide, or, if in the presence of an additional oxidant suchas hydrogen peroxide, tert-butyl hydroperoxide,N-methylmorpholine-N-oxide, or barium chlorate only catalytic amounts ofosmium tetroxide are necessary. Dihydroxylation reactions can be carriedout in a variety of solvents including: 1,4-dioxane, tetrahydrofuran,tert-butanol and diethyl ether, preferably at a temperature of between−15° C. and 15° C.

The resulting glycol can be cleaved by a variety of cleaving reagentsincluding, but not limited to, periodic acid, lead tetraacetate,manganesedioxide, potassium permanganate, sodium metaperiodate, andN-iodosuccinamide. Preferably the cleavage reagent is sodium periodate,the solvent is preferably a mixture of ethanol, methanol or 1,4-dioxaneand water at a temperature of between 0° to 25° C.

As illustrated in Scheme 3, Step B, compounds of formula (3-1) mayundergo reductive amination by treatment with primary or secondaryamines of the formula HN(R₃)(R₄), where R₃ and R₄ are as previouslydefined, optionally in the presence in an acid, followed by treatmentwith a reducing agent, such as NaCNBH₃.

As illustrated in Scheme 4, Compound (1-1) can be treated with analkylating agent of the formula R₁—S(O)₃R_(x) or R₁—X, R_(x) is CF₃— orCH₃—, and X is halogen. Preferred groups for the present processinclude, but are not limited to, propargyl halide, allyl halide,arylallyl halide, heteroarylallyl halide, or benzyl halide. The presentprocess occurs preferably in the presence of a base such as sodiumhydride, potassium hydride, potassium tert-butoxide, potassiumhydroxide, KHMDS, and the like, in an aprotic solvent such as THF, DMSO,DMF, or dioxane, or mixtures thereof, at from about −20° C. to about 60°C. to provide a compound of formula (4-1). The alcohol compound can beconverted to an ether by treatment with an alkylating agent including,but not limited to, alkyl halides, alkyl sulphonates, propargyl halides,allyl halides, arylallyl halides, heteroarylallyl halides, or benzylhalides, in the presence of a base such as sodium hydride, potassiumhydride, potassium tert-butoxide, potassium hydroxide, or KHMDS, in anaprotic solvent such as THF, DMSO, DMF, or dioxane, or mixtures thereofat from −20° C. to 60° C.

Compounds of formula (1-1) can also be treated with an isocyanatereagent of the formula R₁—NCO in an aprotic solvent such as methylenechloride, ethylene chloride, THF, chloroform, DMF, or acetonitrile at atemperature of 0° C. to 50° C. for a period of less than 48 hours, toprovide compound (4-2). In some instances, double addition occursyielding compounds of formula (4-3).

All compounds described herein may be optionally deprotected to formcompounds wherein R_(p) is hydrogen.

Scheme 5 illustrates the processes for the synthesis of compounds offormula (5-1) which are prepared by methods which are well known in theart via compounds of formula (1-1) Compounds of formula (1.1) arereacted with sulfonic anhydride, or sulfonyl chloride in an aproticorganic solvent such as methylene chloride, ethylene chloride, THF,chloroform or the like at a temperature from about −78° C. to about 50°C. for less than 48 hours in the presence of an amine base, such aspyridine, diethylamine, triethylamine or the like, optionally by addinga catalyst such as DMAP, imidazole or the like to provide compounds offormula (5-2) where T is a mesylate or a tosylate. Compounds of formula(5-3) and (5-4) are obtained by treating compounds of formula (5-2) witha base such as DBU, DIEA, triethylamine or the like in solvents such asacetone, DMF, DMSO at a temperature from 25° C. to 100° C. for less than48 hours.

The 2-desmethyl compounds of the present invention may be produced fromthe ketolide of formula (6-1), as illustrated in Scheme 6, or derivedfrom the 2-norerythromycin fermentation product. Compounds of formula(6-1), where R_(e) is selected from hydroxy, halide, sulfone, sulfoxide,sulfide, or selenide, are produced through the treatment with theappropriate electrophilic reagent. The C2-electrophile of compound offormula (6-1) is then eliminated to form compounds of formula (6-2).Compounds of formula (6-2) may subsequently manipulated to formcompounds of formulas (6-3) through (6-7) as illustrated in Scheme 6 viamethods described in U.S. Pat. No. 6,569,836.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —C(O)NH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uand V taken together with the carbon atom to which they are attached areC═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac.

Step 1a. To a solution of compound of formula (1-1, wherein A and Btaken together with the carbon atom to which they are attached areC═N—O—CH₂-pyridyl-pyrazolyl, X and Y taken together with the carbon atomto which they are attached are C═N—Ac, U and V taken together with thecarbon atom to which they are attached are C═O, M and Z are hydrogen, Lis ethyl, W is N(CH₃)₂, and R_(p) is Ac) (prepared according to U.S.application Ser. Nos. 10/429,485 and 10/436,60) (180 mg, 0.22 mmol) inTHF (3 mL) was added trichloroacetyl isocyanate (393 μL, 3.3 mmol) andCuI (catalytic amount) at room temperature. The mixture was stirred for30 mins, then diluted with EtOAc and washed with saturated NaHCO₃solution and brine. The organic solution was dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified bychromatography (silica, hexane:acetone 1:1 and 2:3) to give 170 mg(˜78%) of the desired compound.

MS (ESI) m/z=1070 (M+H)⁺.

Step 1b. A solution of the compound from step 1a in 2N NH₃-methanol washeated at 45° C. for 1.5 hours, evaporated and the residue was purifiedby column chromatography (MeOH: CH₂Cl₂ 2:98 and 4:96) to give 110 mg thetitle compound as a E/Z mixture. HPLC purification gave 35 mg pure Eisomer.

(ESI) m/z=884 (M+H)⁺.

Example 2

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, M is —C(O)NHCH₂CH═CH₂, X andY taken together with the carbon atom to which they are attached areC═N—Ac, U and V taken together with the carbon atom to which they areattached are C═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) ishydrogen.

Step 2a. To a solution of compound of formula (1-1, wherein A and Btaken together with the carbon atom to which they are attached areC═CH₂, X and Y taken together with the carbon atom to which they areattached are C═N—Ac, U and V taken together with the carbon atom towhich they are attached are C═O, M and Z are hydrogen, L is ethyl, W isN(CH₃)₂, and R_(p) is Ac) (prepared according to U.S. application Ser.Nos. 10/429,485 and 10/436,60) (180 mg, 0.25 mmol) in THF (2.5 mL) wasadded allyl isocyanate (126 μL, 1.43 mmol) and CuI (catalytic amount) atroom temperature. The mixture was stirred for about 18 hrs, then another50 μL of the isocyanate was added. The mixture was stirred for another22 hrs at room temperature, then was diluted with CH₂Cl₂ and washed withsaturated NaHCO₃ solution. The organic solution was dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by chromatography (silica, hexane:acetone 4:1) to give 35 mg ofpure the desired product.

MS (ESI) m/z=792 (M+H)⁺.

Step 2b. A solution of the compound from step 2a in methanol is stirredat room temperature for about 16 hours, evaporated give the titlecompound.

MS (ESI) m/z=750 (M+H)⁺.

Example 3

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uis hydrogen, V is OTMS, Z is hydrogen, L is ethyl, W is N(CH₃)₂, andR_(p) is Ac.

Step 3a. To a solution of compound of formula (1-1, wherein A and Btaken together with the carbon atom to which they are attached areC═N—O—CH₂-pyridyl-pyrazolyl, X and Y taken together with the carbon atomto which they are attached are C═N—Ac, U and V taken together with thecarbon atom to which they are attached are C═O, M and Z are hydrogen, Lis ethyl, W is N(CH₃)₂, and R_(p) is Ac) (prepared according to U.S.application Ser. Nos. 10/429,485 and 10/436,60) (4.4 g, 5 mmol) andimidazole (1.36 g, 20 mmol) in 10 mL DMF was added TMSCl (1.9 mL) 15mmol) at room temperature. The mixture was stirred at room temperaturefor 2 hours and quenched with saturated NaHCO₃ (50 mL). The mixture wasextracted with ethyl acetate (60 ml) and washed with brine (50 mL×2) andthe dried over Na₂SO₄. The solvent was removed and the residue ispurified on silica gel column (Hexane:acetone=3:1) to give 3.8 g ofdesired compound.

MS (ESI) m/z=957.68.

Step 3b. A solution of the compound from Step 3a (1.92 g, 2 mmol), allylBoc (632 mg, 4 mmol), Pd₂(dba)₃ (91.6 mg, 0.1 mmol) and dppb (85 mg, 0.2mmol) in 10 mL THF was degassed and heated to reflux. The mixture wasrefluxed for 5 hours and concentrated. The residue was purified via asilica gel column (Hexane:acetone=3:1) to give the title compound (1.6g).

MS (ESI) m/z=997.69.

Example 4

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)]M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uis hydrogen V is OH, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p)is Ac.

To a solution prepared in Example 3 ((1.5 g) in 15 mL of THF) was addedTBAF (1M in THF, 2 mL) and the mixture was stirred at room temperaturefor 2 hours. The solvent was removed and the residue was purified onsilica gel column to give the title compound (1.4 g).

MS (ESI) m/z=925.65.

Example 5

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uand V taken together with the carbon atom to which they are attached areC═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac.

To a solution of the title compound from Example 4 (3.7 g, 4 mmol) inCH₂Cl₂(20 mL) was added HOAc (0.5 mL) and Dess-Martin reagent (2.13 g, 5mmol) at room temperature. The mixture was stirred at room temperaturefor 3 hours and quenched with saturated sodium thiosulfate (50 mL). Theresulting quenched reaction mixture was then extracted with CH₂Cl₂ (50ml) and washed with brine (50 mL×2). The solvent was removed and theresidue was purified on silica gel column to give the title compound(3.1 g).

MS (ESI) m/z=923.45

Example 6

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uand V taken together with the carbon atom to which they are attached areC═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen.

A solution of the title compound of Example 5 (3.0 g) in 50 mL ofmethanol was stirred at 60° C. for 6 hours and concentrated. The residuewas purified on silica gel column to give the title compound (2.8 g).

MS (ESI) m/z=881.45

Example 7

Compounds of formulaes III and IV wherein A and B taken together withthe carbon atom to which they are attached are C═CH₂, M is hydrogen, Xand Y taken together with the carbon atom to which they are attached areC═N—Ac, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen.

Step 7a. Into a solution of imidazole (68 mg, 1.00 mmol) in DMF (1.5 mL)and THF (1.5 mL) was added NaH (30 mg, 60% pure, 0.75 mmol) at 0° C. Themixture was stirred for 30 minutes. Into the reaction mixture, compoundfrom Example 7 (400 mg, 0.50 mmol) was added. The mixture was warmed toroom temperature and stirred overnight. Additional imidazole (23 mg,(0.34 mmol) and NaH (10 mg, 0.25 mmol) were added. The mixture wasstirred at room temperature for 10 more hours. The mixture was taken upin EtOAc, washed with water and then with brine and dried (Na₂SO₄),filtered and concentrated. The resulting crude residue was purified onsilica gel (2M NH₃ in MeOH:CH₂Cl₂, 5:195) to give a 2:3 mixture of thedesired compounds (200 mg, 58%).

MS (ESI) m/z 693 (M+H)⁺.

Step 7b. A solution of a mixture of compounds from step 7a (42 mg) inMeOH (2 mL) was heated to 55° C. for 4 hours. The mixture was cooled toroom temperature and concentrated under reduced pressure. The cruderesidue was purified on HPLC to give a mixture of the title compounds.

MS (ESI) m/z 651 (M+H)⁺.

Example 8

Compounds of formulaes III and IV, wherein A and B taken together withthe carbon atom to which they are attached are C═CH—CH═CH-phenyl, M ishydrogen, X and Y taken together with the carbon atom to which they areattached are C═N—Ac, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac.

A solution of a mixture of compounds from Example 7 (200 mg, 0.29 mmol),β-bromostyrene (106 mg, 0.58 mmol) and K₂CO₃ (160 mg, 1.16 mmol) in DMF(1 mL) was degassed by vacuum/N₂-fill method at −78° C. Into the mixturePOPd (29 mg, 0.058 mmol) was added. The mixture was once again degassedand heated to 100° C. overnight. Additional β-bromostyrene (60 mg, 0.33mmol) was added. The mixture was stirred at 100° C. for 8 hours. Anotherportion of β-bromostyrene (60 mg, 0.33 mmol) and additional POPd (10 mg,0.02 mmol) were added. The mixture was stirred at 100° C. for 1 moreday, cooled to room temperature, diluted with EtOAc, washed with anaqueous solution of saturated NaHCO₃, with brine and dried (Na₂SO₄),filtered and concentrated. The crude residue was purified on silica gel(acetone:hexanes, 60:40) to give the title compounds as an isomericmixture.

MS (ESI) m/z 795 (M+H)⁺.

Example 9

Compounds of formula III and IV, wherein A and B taken together with thecarbon atom to which they are attached are C═CH—CH═CH-phenyl, M ishydrogen, X and Y taken together with the carbon atom to which they areattached are C═N—Ac, W is N(CH₃)₂, and R_(p) is hydrogen.

A solution of a mixture of four isomers from Example 8 (190 mg) in MeOH(3 mL), was stirred at room temperature overnight. MeOH was removedunder reduced pressure. The crude residue was purified by reverse-phaseHPLC to give four different isomers in the amount of 13 mg, 8 mg, 12 mg,20 mg.

MS (ESI) m/z 753 (M+H)⁺.

Example 10

Compounds of formula III, wherein A is OH, B is CH₂OH, M is hydrogen, Xand Y taken together with the carbon atom to which they are attached areC═N—Ac, L is ethyl, W is N(CH₃)₂ and R_(p)═Ac.

Into a solution of a mixture of compounds from Example 8 (40 mg) intert-BuOH (0.2 mL) were added NMO (12.6 mg, 0.093 mmol) and OsO₄ (1 dropof 4% in H₂O). The mixture was stirred at room temperature for 45minutes, taken up in EtOAc, washed with an aqueous solution of saturatedNaHCO₃, then with brine and dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude residue was purified on silica gel (2MNH₃ in MeOH:CH₂Cl₂, 5:195) to give a 1:1 isomeric mixture of the titlecompound (17 mg).

MS (ESI) m/z 727 (M+H)⁺.

Example 11

Compounds of formula III, wherein A is OH, B is CH₂OH, is hydrogen, Xand Y taken together with the carbon atom to which they are attached areC═N—Ac, L is ethyl, W is N(CH₃)₂ and M and R_(p) are hydrogen.

Compound from Example 10 was dissolved in MeOH and stirred at roomtemperature to give the title compound.

Example 12

Compounds of formula II, wherein A, V, and R₂₁ are OH, B is CH₂OH, M andU are hydrogen, X and Y taken together with the carbon atom to whichthey are attached are C═N—Ac, L is ethyl, W is N(CH₃)₂, R₂₀ is methyl,and R_(p)═Ac.

Obtained from the procedure of Example 10 as a 1:1 isomeric mixture (13mg). MS (ESI) m/z 761 (M+H)⁺.

Example 13

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, M is—C(O)N(CH₂CH═CH₂)(CONHCH₂CH═CH₂), X and Y taken together with the carbonatom to which they are attached are C═N—Ac, U and V taken together withthe carbon atom to which they are attached are C═O, Z is F, L is ethyl,W is N(CH₃)₂, and R_(p) is Ac.

To a solution of compound of formula (1-1, wherein A and B takentogether with the carbon atom to which they are attached are C═CH₂, Xand Y taken together with the carbon atom to which they are attached areC═N—Ac, U and V taken together with the carbon atom to which they areattached are C═O, Z=F, M is hydrogen, L is ethyl, W is N(CH₃)₂, andR_(p) is Ac) (prepared according to U.S. application Ser. Nos.10/429,485 and 10/436,60) (200 mg, 0.27 mmol) in THF (2.5 mL) was addedallyl isocyanate (126 μL, 1.43 mmol) and CuI (catalytic amount) at roomtemperature. The mixture was stirred for about 2 hrs, then was dilutedwith CH₂Cl₂ and washed with saturated NaHCO₃ solution. The organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified by chromatography (silica,hexane:acetone 4:1 and 3:2) to give ˜200 mg of the title compound.

MS (ESI) m/z=893 (M+H)⁺.

Example 14

Compound of formula I, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, M is—C(O)N(CH₂CH═CH₂)(CONHCH₂CH═CH₂), X and Y taken together with the carbonatom to which they are attached are C═O, U and V taken together with thecarbon atom to which they are attached are C═O, Z is F, L is ethyl, W isN(CH₃)₂, and R_(p) is hydrogen.

A solution of the compound from Example 13 in THF (2 mL) and 3N HCl (2mL) was heated at 80° C. for about 3 hours, evaporated to give the titlecompound.

MS (ESI) m/z=810 (M+H)⁺.

Example 15

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂OH, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac.

Step 15a. To a mixture of compound of formula (1-1, wherein A and Btaken together with the carbon atom to which they are attached areC═CH₂, X and Y taken together with the carbon atom to which they areattached are C═N—Ac, U and V taken together with the carbon atom towhich they are attached are C═O, M and Z are hydrogen, L is ethyl, W isN(CH₃)₂, and R_(p) is Ac) (prepared according to U.S. application Ser.Nos. 10/429,485 and 10/436,60) (300 mg) in 3 ml of DMF, KO'Bu (75 mg)was added at 0° C. The reaction mixture was stirred at 0° C. for 50 min.phenylselenenyl chloride (135 mg) was then added. The cooling bath wasremoved and the reaction mixture was stirred at RT for 1 hour. Thereaction mixture was then diluted with methylene chloride and washedwith 1M NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, concentrated under vacuo and the residue was purified by flashcolumn chromatography to give 163 mg of the desired product.

[M+H]: 865

Step 15b. The crude mixture from step 15a was dissolved in 20 ml ofTHF/H₂O (1:1). To this mixture was added Oxone (2.0 g). The resultedcloudy mixture was stirred at RT for 30 min. The reaction was thenquenched with sodium bisulfite and extracted with methylene chloride,washed with 1M NaHCO₃, water and brine, dried, filtered and concentratedunder vacuo. The residue was purified by flash column chromatography togive the title compound (273 mg).

[M+H]: 725

Example 16

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂OCH₃, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen.

A solution of compound from Example 15 (20 mg) in methanol was heated to55° C. for 2 hours. The excess methanol was evaporated off under vacuoto give the desired title compound.

[M+H]: 697.

Example 17

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂—NH—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], L is ethyl, Wis N(CH₃)₂, and R_(p) is hydrogen.

To a solution of compound from Example 15 (50 mg) in THF was addedO-(6-pyrazol-1-yl-pyridin-3-ylmethyl)-hydroxylamine hydrochloride(prepared according to patent WO 03/097659) and the resulting mixturewas stirred at room temperature for 2 days. The excess solvent wasremoved under vacuo and the residue was redissolved in methanol and wasallowed to further stirred at room temperature overnight. The excessmethanol was evaporated off and the residue was purified by HPLC to givethe desired title compound.

[M+H]: 855.

Example 18

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═R₂₁═H, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen.

A solution of compound from Example 15 (250 mg) in 10 ml of THF wasadded dropwise into a 1.3 L buffer of 0.2N NaOH in THF/H₂O (1:1) over 30min. After 5 hours, THF was removed in vacuo. The aqueous solution wasextracted with methylene chloride and washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated undervacuo. The residue was purified by flash column chromatography to givethe title compound (100 mg).

[M+H]: 653.

Example 19

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂OH, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac.

Step 19a. A solution of compound of formula (1-1, wherein A and B takentogether with the carbon atom to which they are attached areC═N—O—CH₂-pyridyl-pyrazolyl, X and Y taken together with the carbon atomto which they are attached are C═N—Ac, U and V taken together with thecarbon atom to which they are attached are C═O, M and Z are hydrogen, Lis ethyl, W is N(CH₃)₂, and R_(p) is Ac) (prepared according to U.S.application Ser. Nos. 10/429,485 and 10/436,60) (30 g, 34.0 mmol) inanhydrous DMF (100 ml) was cooled with ice-water bath to 0° C. To thissolution was added solid 60 wt % NaH in mineral oil (2.2 equiv.) inportions. After stirring at 0° C. for 5 min, the ice bath was removedand the resulting suspension was allowed to slowly warm to roomtemperature over 60 min at which point a nice pale yellow slurry wasformed and also no more gas evolution observed. The slurry was cooledback to 0° C. and then was added PhSeCl (1.1 equiv.). The reactionmixture was allowed to stir at 0° C. for 3 hours. After warming up toabout 5-10° C., the reaction mixture was diluted with EtOAc (1.6 L). Themixture was washed with 50% aqueous NH₄Cl solution (450 ml), then withwater (450 ml), dried over MgSO₄, and the organic solution wasevaporated in vacuo to afford the crude product.

The residue was purified by flash column chromatography(acetone/hexanes, 1:1) to afford 70% of the desired selenylatedcompound.

[M+H]: 1039.

Step 19b. To a solution of oxone (10.65 g, 1.2 equiv.) in water (90 ml)at room temperature was slowly added a solution of the selenylatedcompound from step 19a (15.0 g, 1 equiv.) in THF (90 ml) over 10 min.The addition was slightly exothermic. The resulting pale yellowsuspension was stirred at room temperature for an additional 20 min. Thereaction was then quenched with a solution of sodium bisulfite (2.7 g,1.2 equiv.) in water (10-15 ml) at <20° C. (with ice bath) to destroythe excess oxidant. The mixture was further stirred at 20-25° C. for 5min. before saturated aqueous NaHCO₃ solution (120-150 ml) was added toneutralize the mixture to pH 8.5 to 9. The mixture was extracted withEtOAc twice (450 ml+150 ml). The combined organic phase was dried(MgSO₄) and subsequently evaporated in vacuo and the residue waspurified by flash column chromatography eluting with 100% acetone toafford the title compound (8.2 g).

[M+H]: 899.

Example 20

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═R₂₁═H, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac.

To a 3M aqueous KOH solution (5.04 L) was added dropwise a solution ofthe compound from Example 19 (12.6 g) in CH₂Cl₂ (2.52 L) at 20-25° C.over 3.5 hrs. The resulting two-phase reaction mixture was agitatedvigorously at 20-25° C. for 4 hrs. The reaction mixture was neutralizedto a pH of 9.5-10.5 at 20-25° C. by slow addition of 36% HCl. Thetwo-phase mixture was separated. The aqueous layer was extracted withCH₂Cl₂ (1.0 L). The combined organic solution was washed with water(0.75 L) then dried (MgSO₄) and subsequently evaporated in vacuo todryness to afford the crude title compound which was purified by flashcolumn chromatography (acetone/hexanes, 3:1) and then it was furtherpurified by reverse-phase HPLC (20 mM aq. NH₄HCO₃-MeCN) to yield thetitle compound.

[M+H]: 869.

¹³C NMR(CDCl₃, ppm) δ: 201.8, 183.7, 177.1, 162.9, 169.2, 153.4, 150.4,147.6, 141.7, 138.7, 130.3, 126.8, 111.7, 107.4, 100.6, 79.4, 78.3,76.1, 74.7, 73.8, 72.7, 71.2, 68.9, 63.1, 62.7, 62.2, 49.3, 45.0, 40.4,40.0, 38.0, 36.7, 30.3, 24.8, 23.3, 21.2, 20.8, 19.8, 19.0, 17.2, 14.5,13.4, 12.5.

Example 21

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═R₂₁═R_(p)═H, L is ethyl, and W is N(CH₃)₂.

The title compound was prepared with the title compound of Example 20via similar conditions described in Example 16.

[M+H]: 827.

Example 22

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂CH═CH₂, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac.

To a solution of compound from Example 20 in anhydrous THF at 0° C. wasslowly added dropwise 1M KO^(t)BU (1.2 eq.) solution in THF. The mixturewas vigorously stirred at 0° C. for 30 min before a 0.7 M solution ofallyl bromide in THF was slowly added (1.0 equiv.). The resultingmixture was stirred at 0° C. for 60 min. After warming up to about 15°C., the mixture was diluted with EtOAc, washed with 5% aq. NH₄Clsolution, then with water. The organic solution was dried (MgSO₄) andevaporated to dryness and the residue was purified by columnchromatography to give the desired product.

[M+H]: 909.

Example 23

Compound of formula II, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂CH═CH₂, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen.

The title compound was prepared with the title compound of Example 22via similar conditions described in Example 16.

[M+H]: 867.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

1. A compound represented by formulaes:

or their racemates, enantiomers, regioisomers, salts, esters or prodrugsthereof, wherein A and B are independently selected from the groupconsisting of: hydrogen, deuterium, halogen, R₁, OR₁, S(O)_(n)R₁,—NR₁C(O)R₁, —NR₁C(O)NR₃R₄, —NHS(O)_(n)R₁, —CONR₃R₄, and NR₃R₄; R₁ and R₂are independently selected from the group consisting of: hydrogen, acyl,silane, a substituted or unsubstituted, saturated or unsaturatedaliphatic group, a substituted or unsubstituted, saturated orunsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, or asubstituted or unsubstituted heterocyclic group; Each of R₃ and R₄ isindependently selected from the group consisting of: hydrogen, acyl, asubstituted or unsubstituted, saturated or unsaturated aliphatic group,a substituted or unsubstituted, saturated or unsaturated alicyclicgroup, a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, a substituted, or unsubstitutedheterocyclic group; or can be taken together with the nitrogen atom towhich they are attached to form a substituted or unsubstitutedheterocyclic or heteroaromatic ring; Each of R₂₀ and R₂₁ isindependently selected from the group consisting of: hydrogen, acyl, asubstituted or unsubstituted, saturated or unsaturated aliphatic group,a substituted or unsubstituted, saturated or unsaturated alicyclicgroup, a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, a substituted, or unsubstitutedheterocyclic group, provided that R₂₀ and R₂₁ cannot be methyl andhydrogen, methyl and methyl, or methyl and halogen; or R₂₀ and R₂₁ takentogether with the carbon atom to which they are attached form asubstituted or unsubstituted alicylic or substituted or unsubstitutedheterocyclic ring; or A and B, taken together with the carbon atom towhich they are attached, form a substituted or unsubstituted alicyclic,aromatic, heterocyclic or heteroaromatic ring; or A and B, takentogether with the carbon atom to which they are attached, are selectedfrom the group consisting of: CO, C═CHR₁, C═NR₁, C═NOR₁,C═NO(CH₂)_(m)R₁, C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, andC═N—N═CHR₁; M is selected from the group consist of: hydrogen, R₁,C(O)R₁, S(O)_(n)R₁, and C(O)NR₃R₄; provided that M is not hydrogen forcompounds of formula I; L is selected from the group consisting of:hydrogen, a substituted or unsubstituted, saturated or unsaturatedaliphatic group, a substituted or unsubstituted, saturated orunsaturated alicyclic group, a substituted or unsubstituted aromaticgroup, a substituted or unsubstituted heteroaromatic group, and asubstituted or unsubstituted heterocyclic group; X and Y areindependently selected from the group consisting of: hydrogen,deuterium, halogen, R₁, OR₁, S(O)_(n)R₁, —NR₁C(O)R₁, —NR₁C(O)NR₃R₄,—NR₁S(O)_(n)R₁, —C(O)NR₃R₄, and —NR₃R₄; or X and Y, taken together withthe carbon atom to which they are attached, are selected from the groupconsisting of: CO, C═CHR₁, C═NR₁, C═NC(O)R₁, C═NOR₁, C═NO(CH₂)_(m)R₁,C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, C═N— N═CHR₁, C═N—NO₂,and C═N—ONO; one of U or V is hydrogen and the other is independentlyselected from the group

consisting of: R₁, OR₁, OC(O)R₁, OC(O)NR₃R₄, S(O)_(n)R₁, or U and V,taken together with the carbon atom to which they are attached, are C═O;one of J or G is hydrogen and the other is selected from: R₁, OR₁, orNR₃R₄; or, J and G, taken together with the carbon atom to which theyare attached, are selected from: C═O, C═NR₁, C═NOR₁, C═NO(CH₂)_(m)R₁,C═NNHR₁, C═NNHCOR₁, C═NNHCONR₁R₂, C═NNHS(O)_(n)R₁, or C═N—N═CHR₁; W isNR₃R₄; Z is hydrogen, alkyl or halogen; R_(p) is hydrogen, hydroxyprotecting group or hydroxy prodrug group; m is an integer; and n is 0,1, or
 2. 2. A compound of claim 1, wherein A and B taken together withthe carbon atom to which they are attached are C═N—O—CH₂—R₁.
 3. Acompound of claim 2, wherein R₁ is a substituted pyridyl.
 4. A compoundof claim 2, wherein R₁ is a pyridyl substituted with pyrazole.
 5. Acompound of claim 2, wherein R₁ is —C≡C-(pyridyl) or —C≡C— (substitutedpyridyl).
 6. A compound of claim 2, wherein R₁ is —C≡C-(2-aminopyridyl).7. A compound of claim 2, wherein R₁ is a pyridyl substituted with asubstituted pyridyl.
 8. A compound of claim 2, wherein R₁ is asubstituted thiophenyl.
 9. A compound of claim 2, wherein R₁ is athiophenyl substituted with a substituted pyridyl.
 10. A compound ofclaim 1, wherein A and B taken together with the carbon atom to whichthey are attached are C═CH—R₁.
 11. A compound of claim 1, wherein A andB taken together with the carbon atom to which they are attached areC═CH₂.
 12. A compound of claim 1, wherein X and Y taken together withthe carbon atom to which they are attached are C═N—R₁.
 13. A compound ofclaim 1, wherein X and Y taken together with the carbon atom to whichthey are attached are C═N—Ac.
 14. A compound of claim 1, wherein A and Btaken together with the carbon to which they are attached are C═O.
 15. Acompound of claim 1, wherein A and B taken together with the carbon towhich they are attached are C═O and X and Y taken together with thecarbon atom to which they are attached are C═N—R₁.
 16. A compound ofclaim 1, wherein A and B taken together with the carbon to which theyare attached are C═O and X and Y taken together with the carbon atom towhich they are attached are C═N—Ac.
 17. A compound claim 1, wherein Aand B taken together with the carbon to which they are attached are C═O,X and Y taken together with the carbon atom to which they are attachedare C═N—Ac, and W is N(CH₃)₂.
 18. A compound of claim 1, wherein A and Btaken together with the carbon atom to which they are attached areC═N—O—R₁, X and Y taken together with the carbon atom to which they areattached are C═N—R₁, L is ethyl, and W is N(CH₃)₂.
 19. A compound ofclaim 1, wherein A and B taken together with the carbon atom to whichthey are attached are C═N—O—CH₂—R₁, X and Y taken together with thecarbon atom to which they are attached are C═N═R₁, L is ethyl, and W isN(CH₃)₂.
 20. A compound of claim 1 having the formula A:

wherein X, Y, M, L, U, V, Z, W, R_(p) and R₁ are as previously definedin claim
 1. 21. A compound according to claim 1 selected from: (1)compound of formula I, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-pyrazol-1-yl)pyridine)], M is —C(O)NH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uand V taken together with the carbon atom to which they are attached areC═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac; (2)compound of formula I, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, M is —C(O)NHCH₂CH═CH₂, X andY taken together with the carbon atom to which they are attached areC═N—Ac, U and V taken together with the carbon atom to which they areattached are C═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) ishydrogen; (3) compound of formula I, wherein A and B taken together withthe carbon atom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uis hydrogen, V is OH, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p)is Ac; (4) compound of formula I, wherein A and B taken together withthe carbon atom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uis hydrogen, V is OH, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p)is Ac; (5) compound of formula I, wherein A and B taken together withthe carbon atom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uand V taken together with the carbon atom to which they are attached areC═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac; (6)compound of formula I, wherein A and B taken together with the carbonatom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], M is —CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uand V taken together with the carbon atom to which they are attached areC═O, Z is hydrogen, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen; (7)compounds of formulaes III and IV, wherein A and B taken together withthe carbon atom to which they are attached are C═CH₂, M is hydrogen, Xand Y taken together with the carbon atom to which they are attached areC═N—Ac, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen; (8) compoundsof formulaes III and IV, wherein A and B taken together with the carbonatom to which they are attached are C═CH-CH═CH— phenyl, M is hydrogen, Xand Y taken together with the carbon atom to which they are attached areC═N—Ac, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac; (9) compounds offormula III and IV, wherein A and B taken together with the carbon atomto which they are attached are C═CH—CH═CH-phenyl, M is hydrogen, X and Ytaken together with the carbon atom to which they are attached areC═N—Ac, W is N(CH₃)₂, and R_(p) is hydrogen; (10) compounds of formulaIII, wherein A is OH, B is CH₂OH, M is hydrogen, X and Y taken togetherwith the carbon atom to which they are attached are C═N—Ac, L is ethyl,W is N(CH₃)₂ and R_(p)═Ac; (11) compounds of formula III, wherein A isOH, B is CH₂OH, is hydrogen, X and Y taken together with the carbon atomto which they are attached are C═N—Ac, L is ethyl, W is N(CH₃)₂ and Mand R_(p) are hydrogen; (12) compounds of formula II, wherein A, V, andR₂₁ are OH, B is CH₂OH, M and U are hydrogen, X and Y taken togetherwith the carbon atom to which they are attached are C═N—Ac, L is ethyl,W is N(CH₃)₂, R₂₀ is methyl, and R_(p)═Ac; (13) compound of formula I,wherein A and B taken together with the carbon atom to which they areattached are C═CH₂, M is —C(O)N(CH₂CH═CH₂)(CONHCH₂CH═CH₂), X and Y takentogether with the carbon atom to which they are attached are C═N—Ac, Uand V taken together with the carbon atom to which they are attached areC═O, Z is F, L is ethyl, W is N(CH₃)₂, and R_(p) is Ac; (14) compound offormula I, wherein A and B taken together with the carbon atom to whichthey are attached are C═CH₂, M is —C(O)N(CH₂CH═CH₂)(CONHCH₂CH═CH₂), Xand Y taken together with the carbon atom to which they are attached areC═O, U and V taken together with the carbon atom to which they areattached are C═O, Z is F, L is ethyl, W is N(CH₃)₂, and R_(p) ishydrogen; (15) compound of formula II, wherein A and B taken togetherwith the carbon atom to which they are attached are C═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═NAc, Uand V taken together with the carbon atom to which they are attached areC═O, M=R₂₀═H, R₂₁═CH₂OH, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac; (16)compound of formula II, wherein A and B taken together with the carbonatom to which they are attached are C═CH₂, X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂OCH₃, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen;(17) compound of formula II, wherein A and B taken together with thecarbon atom to which they are attached are C═CH₂, X and Y taken togetherwith the carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂—NH—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], L is ethyl, Wis N(CH₃)₂, and R_(p) is hydrogen; (18) compound of formula II, whereinA and B taken together with the carbon atom to which they are attachedare C═CH₂, X and Y taken together with the carbon atom to which they areattached are C═NAc, U and V taken together with the carbon atom to whichthey are attached are C═O, M=R₂₀═R₂₁═H, L is ethyl, W is N(CH₃)₂, andR_(p) is hydrogen; (19) compound of formula II, wherein A and B takentogether with the carbon atom to which they are attached areC═N—O—CH₂-[5-(2-pyrazol-1-yl)pyridine)], X and Y taken together with thecarbon atom to which they are attached are C═NAc, U and V taken togetherwith the carbon atom to which they are attached are C═O, M=R₂₀═H,R₂₁═CH₂OH, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac; (20) compound offormula II, wherein A and B taken together with the carbon atom to whichthey are attached are C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Ytaken together with the carbon atom to which they are attached areC═NAc, U and V taken together with the carbon atom to which they areattached are C═O, M=R₂₀═R₂₁═H, L is ethyl, W is N(CH₃)₂, and R_(p)═Ac;(21) compound of formula II, wherein A and B taken together with thecarbon atom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═R₂₁═R_(p)═H, L is ethyl, and W is N(CH₃)₂; (22) compound offormula II, wherein A and B taken together with the carbon atom to whichthey are attached are C═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Ytaken together with the carbon atom to which they are attached areC═NAc, U and V taken together with the carbon atom to which they areattached are C═O, M=R₂₀═H, R₂₁═CH₂CH═CH₂, L is ethyl, W is N(CH₃)₂, andR_(p)═Ac; (23) compound of formula II, wherein A and B taken togetherwith the carbon atom to which they are attached areC═N—O—CH₂-[5-(2-(pyrazol-1-yl)pyridine)], X and Y taken together withthe carbon atom to which they are attached are C═NAc, U and V takentogether with the carbon atom to which they are attached are C═O,M=R₂₀═H, R₂₁═CH₂CH═CH₂, L is ethyl, W is N(CH₃)₂, and R_(p) is hydrogen.22. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically-acceptable salt,ester or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier.
 23. A method for treating a bacterial infection in asubject in need of such treatment, comprising administering to saidsubject a therapeutically-effective amount of a pharmaceuticalcomposition according to claim
 22. 24. A method of treating cysticfibrosis in a patient, comprising administering to said subject, atherapeutically effective amount of a pharmaceutical composition ofclaim
 22. 25. A method of treating inflammation in a subject comprisingadministering to said subject, therapeutically effective amount of apharmaceutical composition of claim 22.